2.1 Kaposi Sarcoma
KS is a cancer that develops from the cells that line lymph or blood vessels. It was first described in 1872 by the Hungarian dermatologist Moritz Kaposi. Before the advent of widespread infection with the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS) epidemic, it was considered a rare condition.
Most KS cases in the US develop in people infected with HIV. It has been estimated that an HIV-infected person has a 20,000-fold increased risk of developing KS compared with people without HIV. AIDS patients with KS increased the rate of KS in the US more than 20 times, peaking at 47 cases per million people (per year) in the early 1990s. Early in the AIDS epidemic, patients infected with HIV in the US were estimated to have a 1 in 2 chance of developing KS. With new treatments for AIDS, KS has become less common in the US, with about 7 cases per million people each year (American Cancer Society website; www.cancer.org/docroot/CRI/CRI—2—3x.asp?dt=21; information last revised Mar. 14, 2006).
KS cells form purple, brown or red lesions on the skin that are usually papular (i.e, palpable or raised). In many cases, these skin lesions do not cause any symptoms; in other cases, they may cause painful swelling, especially in the legs, groin area or skin around the eyes. KS can cause serious problems, and can even become life-threatening when the lesions are in the lungs, liver or digestive tracts. Lesions in the digestive tract may cause blockage, resulting in nausea, vomiting, abdominal pain and occasionally bleeding. Lesions in the lungs can cause difficulty breathing.
KS is caused by the KS herpesvirus (KSHV), which is also called human herpesvirus 8. Infection with KSHV is necessary, but insufficient for KS development. KSHV is more prevalent in the HIV-infected population than in the general population in the US. Contributing factors, such as immunosuppression and AIDS, as well as others, are required for disease development (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44).
KSHV infection is much more common in some parts of the world, such as subequatorial Africa, where over 30% of the population carries KSHV antibodies. In some areas in Africa, the virus seems to spread from mother to child. Seropositivity for the virus ranges from 10% to 25% in the Mediterranean area. In other regions of the world where KSHV is not endemic, the seroprevalence is around 2-5%. (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44).
KSHV appears to be transmitted through saliva, as is the case for other human herpesviruses. Sexual transmission through semen has also been suggested (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44). The virus may also be transmitted through organ donation. Some cases of KSHV have been reported in injection drug users and are thought to be spread when needles are contaminated with infected blood. The transmission of KSHV through blood appears to be rare and occurs much less than HIV transmission.
KSHV has a long latency period, like most herpesviruses. Several KSHV genes show oncogenic properties, modifying cell proliferation, apoptosis and angiogenesis. Proteins encoded by these genes, such as vGPCR, LANA-1, vCyclin, vFLIP and vIL-6 play an important role in the pathogenesis of KS (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44).
2.2 Types of Kaposi Sarcoma
The different types of KS are defined by the different populations in which the disease develops, but the changes within the KS cells are very similar.
Classic (or Mediterranean) KS occurs in elderly people of Mediterranean, Eastern European, and Middle Eastern heritage and occurs more commonly in men than in women. Patients typically have one or more lesions on the legs, ankles, or the soles of the feet. In comparison with other types of KS, the lesions in this type do not grow as quickly, and new lesions do not develop as often. People who get classic KS come from areas where KSHV infection is more common than in the US or Northern Europe. The immune system of people with classic KS is not as weakened as those who have epidemic KS (see below); however, old age may naturally weaken the immune system, thus making people more likely to develop KS if they already have a KSHV infection.
Endemic KS occurs in people living in Equatorial Africa and is sometimes called African KS. KSHV infection is much more common in Africa than in other parts of the world, increasing the chance of developing KS. There appear to be other factors in Africa that contribute to the development of KS since the disease affects a broader group of people that includes children and women. Endemic KS tends to occur in younger people (usually under age 40). Rarely, a more aggressive form of endemic KS is seen in children before puberty. This type usually affects the lymph nodes and other organs and can lead to death within a year. In some parts of Africa, KS is currently considered the most common cancer (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44).
The most common type of KS in the United States is epidemic or AIDS-related KS. This type of KS develops in individuals who are infected with HIV, the virus that causes AIDS. The severe immunosuppression caused by AIDS increases the likelihood of the development of KS in individuals already infected with KSHV. This more aggressive form of KS was first noted in young homosexual men in the 1970s. In addition to departing from the usual ethnic predisposition, the disease manifested with lesions that occurred at any site and that tended to spread more rapidly to the lymph nodes and visceral organs, such as the gastrointestinal and respiratory tracts (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44). Gastrointestinal (GI) involvement is generally asymptomatic and does not affect prognosis, while lung involvement frequently is symptomatic and adversely affects prognosis (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). The disease progressed very rapidly and many patients died within one year, despite drug chemotherapy regimens (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44). Treatment of HIV infection with highly active antiretroviral therapy (HAART) has decreased the incidence of epidemic KS and can often keep advanced KS from developing. The clinical course of AIDS-KS is variable, ranging from a very indolent process requiring little, if any therapy, to a rapidly progressive and fatal disease (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455).
When KS develops in people whose immune systems have been suppressed after an organ transplant it is called iatrogenic, or transplant-associated KS or immunosuppression-associated KS. Most transplant patients take immunosuppressant drugs, such as rapamycin, to prevent organ rejection. The immunosuppression caused by these drugs increases the likelihood that individuals infected with KSHV will develop KS. Stopping the immune suppressing drugs or lowering their dose often makes KS lesions disappear or get smaller.
2.3 Histogenesis and Diagnosis of Kaposi Sarcoma
Despite its name, KS is not considered a true sarcoma, which comprises a tumor arising from the mesenchymal tissue. KS is a highly vascular tumor that arises as a cancer of the lymphatic endothelium. Tumors have dense vascular channels that leak blood cells into the surrounding tissue, giving the tumor its dark color and characteristic bruise-like appearance. KS lesions contain tumor cells with a characteristic abnormal elongated shape, called spindle cells. KSHV proteins are detected in spindle cells.
The first sign of KS is usually the development of skin lesions. The lesions can develop anywhere in the body, but most often, they arise on the legs, nose, feet, external portions of the ears, mouth or genitals. About 1 in 3 people with AIDS-related KS will develop mouth and throat lesions. KS lesions are often present in the GI tract when the patient is first diagnosed, particularly if the immune system is severely suppressed, due to AIDS. Sometimes lesions in the GI tract can develop in the absence of skin lesions. While often asymptomatic, lesions in the GI tract may lead to bowel obstruction and require surgery to unblock the intestine. Swelling of the lymph nodes, called lymphedema, due to blockage caused by KS, can also occur in the absence of skin lesions.
The histopathologic features of all four variants of KS are indistinguishable and the diagnosis using histology differs according to the stage and form of KS (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44). A biopsy will reveal the presence of the spindle cells in suspected KS lesions. In addition, bronchoscopy can be performed if KS is suspected in the lungs. Gastrointestinal endoscopy can be performed if KS is suspected in the GI tract.
Immunohistochemistry has become the standard for identifying KS, as it is easier and more reliable than other methods. The LANA-1 monoclonal antibody allows the identification of all types of lesions and KSHV-positive lymphomas. Polymerase-chain reaction has been extensively used as a method to identify KSHV. In situ hybridization (ISH) may also be used for the detection of KSHV sequences (Horenstein et al., 2008; J. Cutan. Pathol. 35(Suppl. 2): 40-44).
Unlike most other forms of cancer, there is no officially accepted system for staging all types of KS. Most types of cancer staging systems are based mostly on the size of the primary lesion and how far the cancer has spread from that lesion. KS doesn't generally develop just in a single area so this staging approach isn't used.
The AIDS Clinical Trials Group (ACTG) system for KS in AIDS patients was developed to predict survival and treatment outcome. The outlook for patients with AIDS-related KS is influenced at least as much by their immunological status and the presence of other HIV-related illnesses, as by the tumor burden itself (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). For this reason, the ACTG system uses the “TIS” staging criteria (tumor, immunological status and systemic illnesses). The three criteria consist of:
1) the extent of the tumor (T);
2) the status of the immune system (I), as measured by the number of CD4 cells; and
3) the extent of involvement within the body or systemic illness (S).
Under each heading, there are two subgroups identified by either a zero (0), which means good risk or a one (1), which means poor risk.
2.4 Treatment of Kaposi Sarcoma
KS is not curable, but it can be effectively palliated for many years, and this is typically the aim of current treatments. Treatment for KS is more effective today than it was a couple of decades ago. Choices about the best treatment options for each patient are based on the function of the immune system, as well as the number, location and size of the KS lesions. The patient's general condition is also a major factor. The presence and severity of other serious medical conditions can make some treatments a poor choice. Surgery is generally not recommended, as KS can appear in wound edges.
Treatment of any immunodeficiency and/or related infections is a very important part of the treatment of KS. Therefore, effective treatment of AIDS patients with highly active antiretroviral therapy (HAART) is associated with regression in size and number of existing lesions. For many patients with KS, HAART may be the only treatment needed for the cancer. The risk of developing new lesions is lower when antiviral medicines such as ganciclovir or foscarnet are used in patients who test positive for KSHV. However, existing lesions are relatively resistant to treatment with antiviral agents. Patients presenting with AIDS-KS often have other opportunistic life-threatening diseases. The prevention and effective treatment of these diseases, such as bacterial infections, is also important in slowing down the progression of KS.
Local treatment is most useful when there are just a few lesions in a very visible area, such as the face. The drawback of local therapy is that it doesn't keep lesions from developing.
Local treatment includes topical treatment with alitretinoin, a first-generation retinoid, available as a gel under the name Panretin®. Another type of local treatment is cryosurgery, whereby a probe cooled with liquid nitrogen is used to freeze the lesion. Photodynamic treatment is also an option for KS patients. In this case, patients are given a drug that has greater build-up in tumor cells than in normal cells. About 48 hours after the patient takes the drug, light is used to activate the drug and kill the cancer cells.
Intralesional chemotherapy, whereby a small amount of a chemotherapy drug is injected directly into the KS lesion, allows patients to avoid many of the typical side effects seen with systemic chemotherapy. The most common drug used for intralesional chemotherapy in KS is called vinblastine.
Similar to local treatment, radiation therapy can be used to treat KS when the disease is only in a few areas. Radiation treatments are used to reduce symptoms like pain and swelling, as well as to treat lesions that are unsightly. Radiation treatment can induce side effects, such as skin changes, nausea, vomiting and fatigue.
In general, systemic treatment for KS is indicated in patients with rapidly progressive mucocutaneous disease, causing lymphedema, ulceration and pain, as well as those with symptomatic visceral involvement and/or pulmonary involvement and debilitating KS-related symptoms (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). Many chemotherapeutic agents have been tested and used in treatment of AIDS-KS, either as a single therapy or as a combination therapy. Even without the use of HAART, response rates of KS to single agents have varied widely, from 21% to 80% and the median duration of response varies from 1 to 9 months (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455).
Liposomal anthracyclines are used most often to treat KS. This formulation has been developed to prolong anthracyline circulation time in plasma and decrease their toxicity. The two liposomal anthracyclines used in the US to treat KS are doxorubicin (Doxil®) and daunorubicin (DaunoXome®). These drugs have become the first choice for KS treatment, especially in advanced or rapidly proliferating AIDS-KS, and have been used in several studies in AIDS-KS patients (Vanni et al., 2006, Cancer Treatment Reviews; 32:445-455). Overall, liposomal anthracyclines have good efficacy and are generally well tolerated. Myelosuppression remains the most important dose-limiting toxicity; neuropathy and alopecia occur infrequently and anthracycline-induced cardiotoxicity is rare.
Other chemotherapy drugs that are used to treat KS include paclitaxel (Taxol®) and vinorelbine (Navelbine). Paclitaxel is a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly effective in the treatment of certain neoplasms. It has been the subject of several studies with AIDS-KS patients (Vanni et al., 2006, Cancer Treatment Reviews; 32:445-455). Paclitaxel is well tolerated, but the higher prevalence rates of alopecia, myalgia, arthralgia and bone marrow suppression make it less attractive than liposomal anthracyclines as initial treatment for disseminated KS (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455).
Other chemotherapy drugs that have been used in the past include bleomycin, vinblastine, vincristine and etoposide. Several combination have been investigated using these drugs (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). The combination of vincristine and bleomycin with or without doxorubicin (ABV or BV) has been supplanted by liposomal anthracyclines and paclitaxel for reasons of efficacy and toxicity. These chemotherapeutic agents have also been evaluated as single therapy in AIDS-KS patients (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). Etoposide was one of the first drugs shown to be active against AIDS-KS. These drugs are still used in many developing countries where liposomal anthracyclines and paclitaxel are too costly and/or unavailable, and where the bulk of AIDS-KS cases exist (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). Response rates for these agents have varied widely in these studies. Reasons for the variation in response rates may be the different prognostic factors of the patients enrolled, the lack of universally applied criteria for evaluation of response and the differences in the number of patients enrolled (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). Most of the studies using the “old” chemotherapeutic agents were conducted in the pre-HAART era. Therefore, one can speculate that these response rates may become higher in AIDS-KS patients who are being treated with HAART.
Interferon has been seen as an attractive treatment option since the early AIDS-KS cases. The response rate to interferon as a single agent, in selected populations, varies from 20% to 60% (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). In appropriately selected patients, the duration of the response can be relatively long, and could average 6-12 months for partial responders and up to 2 years for complete responders. However, interferon is not an appropriate therapy for patients with rapidly progressive KS, debilitating symptoms or symptomatic visceral disease, as the time to response is relatively long (8-12 weeks) (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). In addition, myelosuppression, frequent hepatic toxicity and constitutional symptoms limit its use.
2.4.1 Role of HAART in AIDS-KS Treatment
The incidence of KS among patients infected with HIV has diminished since the beginning of the HAART era. Recent studies have shown that AIDS-KS in patients receiving HAART manifests less aggressively than in patients not on HAART (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). HAART has also been associated with longer survival time and longer time to treatment failure in patients who have received chemotherapy (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). HAART is often the only anti-cancer therapy in the early stages of the disease (T0) and/or for slowly proliferating disease. When patients develop rapidly proliferating disease, chemotherapy is used as a first-line therapy with or without anti-retroviral therapy, followed by maintenance with HAART (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). Thus, HAART may be useful for the less aggressive stage of the disease as well as the more advanced stage of the disease as a maintenance therapy.
Two studies have shown that non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART is as effective as protease inhibitor-based HAART in preventing KS (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455). It has been suggested that protease inhibitor-based therapy, in addition to controlling HIV viral load and restoring patients' immunity, may contribute directly to tumor regression. Nude mice treated with similar doses of two protease inhibitors, indinavir and saquinavir, as AIDS patients, demonstrated a reduction in the number and size of macroscopic KS-like angioproliferative lesions (Sgadari et al., 2003. Lancet Oncol. 4: 537-47). Another protease inhibitor, ritonavir, demonstrated in-vitro inhibition of activation and proliferation of primary endothelial cells and decreased production of TNF-α, IL-6, IL-8 and VEGF (Pati et al., 2002. Blood. 99:3771-3779).
It appears that HAART may also contribute to KSHV latency. Uncontrolled HIV replication leads to the expression of the HIV Tat protein, which in turn regulates KSHV growth. Reduction of the viral load with HAART will thus lead to a reduction in the expression of the Tat protein, which in turn will result in KSHV latency and tumor regression. (Vanni et al., 2006; Cancer Treatment Reviews; 32:445-455).